WO2023174408A1 - Pharmaceutical combination of anti-tim-3 antibody and anti-pd-l1 antibody - Google Patents

Abstract

Provided is a pharmaceutical combination of an anti-TIM-3 antibody and an anti-PD-L1 antibody, which pharmaceutical combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof. Also provided is a kit for treating tumors, which kit comprises the pharmaceutical combination. In addition, further provided are the use of the pharmaceutical combination in the preparation of a drug for treating tumors, and a method for treating tumors by means of the pharmaceutical combination.

Description

Drug combination of anti-TIM-3 antibody and anti-PD-L1 antibody Technical field

The present disclosure belongs to the field of biomedicine, and specifically relates to a pharmaceutical combination of anti-TIM-3 antibodies and anti-PD-L1 antibodies.

Background technique

In recent years, the incidence of cancer has been on the rise, the treatment effect of malignant tumors is poor, and the rate of late metastasis is high. Although conventional clinical treatments such as radiotherapy, chemotherapy and surgery can relieve pain and prolong survival time, they all have limitations. Therefore, immunotherapy that kills tumor cells by inhibiting immune checkpoints, reactivating immune cells, avoiding immune escape of tumor cells, has gradually become a hot spot in the field of tumor treatment.

T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), also known as Hepatitis A Virus Cellular Receptor 2 (HAVCR2) , is a member of the TIM family of immunomodulatory proteins (the human TIM family includes TIM-1, 3, and 4). TIM-3 is selectively expressed on the surface of activated Th1 cells, and is also expressed on myeloid cells, DC cells, NK cells, and macrophages. It is also expressed on a variety of tumor cells, such as melanoma, cervical cancer and renal cancer. TIM-3 has a variety of different ligands, including galectin 9 (Galectin9), phosphatidylserine (PtdSer), high mobility group protein B1 (HMGB1) and carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1). As an immune checkpoint, TIM-3's physiological function is to negatively regulate the body's immune function and avoid damage to the body caused by excessive immunity or autoimmunity. Increasing evidence shows that TIM-3 protein and/or mRNA is up-regulated on a variety of tumor tissues and tumor-related immune cells, participates in tumor immune evasion and immune response, and promotes tumor development.

Programmed death-ligand 1 (PD-L1) is a ligand of programmed death molecule 1 (Programmed death, PD-1). It is highly expressed on the surface of various malignant tumor cells, and the expression level is The clinical manifestations and prognosis of the subjects are closely related. In the tumor microenvironment, PD-L1 on the surface of cancer cells inhibits the activation and proliferation of T cells by binding to PD-1 or CD80 on the surface of T cells, promotes effector T cells to enter a state of exhaustion or anergy, and induces T cell Apoptosis stimulates helper T cells to differentiate into regulatory T cells, thereby preventing T cells from killing tumor cells. Anti-PD-L1 antibodies can prevent the activity of effector T cells in the tumor microenvironment from being inhibited and enhance the endogenous anti-tumor immune effect by blocking the interaction between PD-L1, PD-1 and CD80.

TIM-3 is closely related to PD-1/PD-L1, and TIM-3 may be an important molecule that mediates PD-1/PD-L1 to achieve immune evasion. However, monotherapy with anti-TIM-3 antibodies and anti-PD-L1 antibodies still has certain limitations, and other alternative therapies are needed, such as combining anti-TIM-3 antibodies with anti-PD-L1 antibodies, to improve the anti-tumor effect.

Summary of the invention

In one aspect, the present disclosure provides a pharmaceutical combination comprising an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-L1 antibody, or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination includes a unit dose of 60-1800 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and a unit dose of 10-1800 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination comprises 100-1800 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and 100-2400 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle, comprising 100-1800 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and 100-2400 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof .

In some embodiments, the pharmaceutical combination is used to treat tumors.

In another aspect, the present disclosure provides a pharmaceutical combination for treating tumors, comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof.

In another aspect, the present disclosure also provides a method of treating a tumor in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination of the present disclosure. In addition, the present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the preparation of medicaments for treating tumors. Alternatively, the present disclosure also provides the use of anti-TIM-3 antibodies or antigen-binding fragments thereof and anti-PD-L1 antibodies or antigen-binding fragments thereof in the preparation of medicaments for treating tumors.

In some embodiments, the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof, may be packaged separately or together. And wherein, the anti-TIM-3 antibody or antigen-binding fragment thereof can be packaged in a single portion or multiple equal portions, and the anti-PD-L1 antibody or antigen-binding fragment thereof can be packaged in a single portion or multiple portions.

In some embodiments, the pharmaceutical combination is a fixed combination. In some embodiments, the fixed combination is in the form of a solid formulation or a liquid formulation.

In some embodiments, the pharmaceutical combination is a non-fixed combination. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof in the non-fixed combination are each in the form of a pharmaceutical composition.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof can be administered simultaneously, sequentially, and/or alternately.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100-1800 mg each time.

In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 100-2400 mg each time.

In another aspect, the present disclosure provides kits for treating tumors, comprising a pharmaceutical combination of the present disclosure. In some specific embodiments, the kit includes an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-L1 antibody or antigen-binding fragment thereof.

In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is lung cancer. In some embodiments, the lung cancer is selected from non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).

Detailed description of the invention

The present disclosure provides pharmaceutical combinations comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is used to treat tumors.

The present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the preparation of a medicament for treating tumors. The present disclosure also provides the use of the pharmaceutical combination of the present disclosure to treat tumors. The present disclosure also provides methods of treating tumors, comprising administering to a subject a therapeutically effective amount of a pharmaceutical combination of the present disclosure.

The present disclosure also provides kits for treating tumors, the kits comprising pharmaceutical combinations of the present disclosure. In some embodiments, the kit further includes instructions for treating tumors with the pharmaceutical combination of the present disclosure.

In addition, the present disclosure also provides anti-TIM-3 antibodies or antigen-binding fragments thereof for treating tumors. The present disclosure also provides the use of an anti-TIM-3 antibody or antigen-binding fragment thereof in the preparation of a medicament for treating tumors. The present disclosure also provides the use of anti-TIM-3 antibodies or antigen-binding fragments thereof to treat tumors. The present disclosure also provides methods of treating tumors, comprising administering to a subject a therapeutically effective amount of an anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure.

In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is lung cancer. In some embodiments, the lung cancer is selected from non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).

drug combination

In one aspect, the present disclosure provides a pharmaceutical combination comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-L1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination is packaged in the same kit, which further includes the combination of an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-L1 antibody or antigen-binding fragment thereof to treat tumors. instruction of. In other embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof in the pharmaceutical combination are separately packaged in respective kits, and the kit further includes Instructions for the combined use of anti-TIM-3 antibodies or antigen-binding fragments thereof and anti-PD-L1 antibodies or antigen-binding fragments thereof to treat tumors.

In some embodiments, the pharmaceutical combination is a fixed combination. In some embodiments, the fixed combination is in the form of a solid formulation or a liquid formulation. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof in the fixed combination are formulated in a single formulation. In some embodiments, the single formulation is in the form of a liquid formulation or a solid formulation. In some specific embodiments, the single formulation is an injectable solution. In some specific embodiments, the single formulation is a lyophilized formulation.

In some embodiments, the pharmaceutical combination is a non-fixed combination. In some embodiments, the anti-TIM-3 in the non-fixed combination The antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition, and the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof and the pharmaceutical composition containing the anti-PD-L1 antibody or its antigen-binding fragment are each in the form of a pharmaceutical composition. The pharmaceutical composition of the antigen-binding fragment may or may not be present in the same pharmaceutical bag.

In some specific embodiments, in the non-fixed combination, the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof is a liquid preparation. In some specific embodiments, the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is an injectable solution. In some specific embodiments, pharmaceutical compositions containing anti-TIM-3 antibodies or antigen-binding fragments thereof are lyophilized formulations. In some specific embodiments, in the non-fixed combination, the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is a liquid preparation. In some specific embodiments, the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is an injection. In some specific embodiments, the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is a lyophilized preparation.

In some embodiments, the unit dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg. In some embodiments, the unit dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 60 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320mg, about 360mg, about 400mg, about 420mg, about 440mg, about 480mg, about 520mg, about 540mg, about 560mg, about 600mg, about 640mg, about 660mg, about 680mg, about 720mg, about 760mg, about 780mg, about 800mg, About 840mg, about 880mg, about 900mg, about 920mg, about 960mg, about 1000mg, about 1020mg, about 1040mg, about 1080mg, about 1120mg, about 1140mg, about 1160mg, about 1200mg, about 1240mg, about 1260mg, about 1280mg, about 1320mg , about 1360mg, about 1380mg, about 1400mg, about 1440mg, about 1480mg, about 1500mg, about 1520mg, about 1560mg, about 1600mg, about 1620mg, about 1640mg, about 1680mg, about 1720mg, about 1740mg, about 1760mg and/or about 1800mg , or a range formed by any of the above values. In some embodiments, the unit dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 240 mg, about 300 mg, about 360 mg, and/or about 600 mg. In some embodiments, the unit dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 240 mg and/or about 600 mg.

In some embodiments, the unit dosage of the anti-PD-L1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 10-1800 mg, 100-1500 mg, 100-1200 mg, 600-1200 mg, or 100-600 mg. In some embodiments, the unit dose of the anti-PD-L1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 10 mg, about 40 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200mg, about 220mg, about 240mg, about 260mg, about 280mg, about 300mg, about 320mg, about 340mg, about 360mg, about 380mg, about 400mg, about 420mg, about 440mg, about 460mg, about 480mg, about 500mg, about 520mg, About 540mg, about 560mg, about 580mg, about 600mg, about 620mg, about 640mg, about 660mg, about 680mg, about 700mg, about 720mg, about 740mg, about 760mg, about 780mg, about 800mg, about 820mg, about 840mg, about 860mg , about 880mg, about 900mg, about 920mg, about 940mg, about 960mg, about 980mg, about 1000mg, about 1020mg, about 1040mg, about 1060mg, about 1080mg, about 1100mg, about 1120mg, about 1140mg, about 1160mg, about 1180mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg and/or about 1800 mg, or a range formed by any of the above values. In some embodiments, the unit dosage of the anti-PD-L1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 100 mg and/or about 600 mg.

In some embodiments, the pharmaceutical combination includes a unit dose of 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and a unit dose of 10 -1800 mg, 100-1500 mg, 100-1200 mg, 600-1200 mg, or 100-600 mg of anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination includes a unit dose of about 60 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320 mg, about 360 mg, about 400 mg, about 420 mg, About 440mg, about 480mg, about 520mg, about 540mg, about 560mg, about 600mg, about 640mg, about 660mg, about 680mg, about 720mg, about 760mg, about 780mg, about 800mg, about 840mg, about 880mg, about 900mg, about 920mg , about 960mg, about 1000mg, about 1020mg, about 1040mg, about 1080mg, about 1120mg, about 1140mg, about 1160mg, about 1200mg, about 1240mg, about 1260mg, about 1280mg, about 1320mg, about 1360mg, about 1380mg, about 1400mg, about Anti-TIM in the range of 1440 mg, about 1480 mg, about 1500 mg, about 1520 mg, about 1560 mg, about 1600 mg, about 1620 mg, about 1640 mg, about 1680 mg, about 1720 mg, about 1740 mg, about 1760 mg and/or about 1800 mg, or any of the above values. -3 antibody or antigen-binding fragment thereof, and a unit dose of about 10 mg, about 40 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280mg, about 300mg, about 320mg, about 340mg, about 360mg, about 380mg, about 400mg, about 420mg, About 440mg, about 460mg, about 480mg, about 500mg, about 520mg, about 540mg, about 560mg, about 580mg, about 600mg, about 620mg, about 640mg, about 660mg, about 680mg, about 700mg, about 720mg, about 740mg, about 760mg , about 780mg, about 800mg, about 820mg, about 840mg, about 860mg, about 880mg, about 900mg, about 920mg, about 940mg, about 960mg, about 980mg, about 1000mg, about 1020mg, about 1040mg, about 1060mg, about 1080mg, about 1100 mg, about 1120 mg, about 1140 mg, about 1160 mg, about 1180 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg and/or about 1800 mg, or an anti-PD-L1 antibody in the range formed by any of the above values or antigen-binding fragments thereof. In some embodiments, the pharmaceutical combination includes a unit dose of about 240 mg, about 300 mg, about 360 mg, and/or about 600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and a unit dose of about 100 mg and/or about 600 mg. Anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination includes a unit dose of about 240 mg and/or about 600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and a unit dose of about 100 mg and/or about 600 mg of an anti-PD-L1 antibody or Its antigen-binding fragment.

In some embodiments, the pharmaceutical combination comprises 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, An anti-TIM-3 antibody or an antigen-binding fragment thereof in the range of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or any of the above values. In some embodiments, the pharmaceutical combination comprises about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination comprises 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, About 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, or about 2400 mg, or an anti-PD-L1 antibody or its antigen in the range formed by any of the above values Combine fragments. In some embodiments, the pharmaceutical combination comprises about 1200 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination comprises 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, and 100-2400 mg, 600-1800 mg, 1000- 1500 mg, 1000-1200 mg, or 1200-1500 mg of anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, About 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or an anti-TIM-3 antibody or an antigen-binding fragment thereof within a range formed by any of the above values, and about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, About 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg , about 2300 mg, or about 2400 mg, or an anti-PD-L1 antibody or an antigen-binding fragment thereof within a range formed by any of the above values. In some embodiments, the pharmaceutical combination comprises about 1200 mg or about 1500 mg of an anti-TIM-3 antibody, or antigen-binding fragment thereof, and about 1200 mg of an anti-PD-L1 antibody, or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and contains 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle, comprising about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg , about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or an anti-TIM-3 antibody or an antigen-binding fragment thereof within a range formed by any of the above values. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and contains about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and contains 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg of an anti-PD-L1 antibody or antigen thereof Combine fragments. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle, comprising about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg , about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, About 2200 mg, about 2300 mg, or about 2400 mg, or an anti-PD-L1 antibody or an antigen-binding fragment thereof within a range formed by any of the above values. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and contains about 1200 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and contains 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, and 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg of anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle, comprising about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg , about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or an anti-TIM-3 antibody or an antigen-binding fragment thereof within a range formed by any of the above values, and about 100 mg, about 200 mg , about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, or about 2400 mg, or an anti-PD-L1 antibody or an antigen-binding fragment thereof within a range formed by any of the above values. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and comprises about 1200 mg or about 1500 mg of an anti-TIM-3 antibody, or an antigen-binding fragment thereof, and about 1200 mg of an anti-PD-L1 antibody, or an antigen-binding fragment thereof. fragment.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof can be a pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof. Wherein, the pharmaceutical composition containing anti-TIM-3 antibody or antigen-binding fragment thereof is a single dose or multiple doses, preferably multiple doses. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing about 240 mg, about 300 mg, about 360 mg, and/or about 600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing about 240 mg and/or about 600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof.

In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof may be a pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof. Wherein, the pharmaceutical composition containing anti-PD-L1 antibody or antigen-binding fragment thereof is a single dose or multiple doses, preferably multiple doses. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing about 100 mg and/or about 600 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof.

In some embodiments, the dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a fixed dosage in the pharmaceutical composition.

In some embodiments, the pharmaceutical combination contains an anti-TIM-3 antibody or antigen-binding fragment thereof in a daily dose. In some embodiments, the pharmaceutical combination contains the anti-TIM-3 antibody or antigen-binding fragment thereof in a once-daily dose.

In some embodiments, the pharmaceutical combination contains a uniform dose of the anti-TIM-3 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination contains an amount of anti-TIM-3 antibody or antigen-binding fragment thereof that is sufficient for one treatment cycle, and each treatment cycle is 21 days (ie, 3 weeks).

In some embodiments, the dosage of the anti-PD-L1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a fixed dosage in the pharmaceutical composition.

In some embodiments, the pharmaceutical combination contains a daily dose of the anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination contains the anti-PD-L1 antibody or antigen-binding fragment thereof in a once-daily dose.

In some embodiments, the pharmaceutical combination contains a uniform dose of the anti-PD-L1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination contains an amount of anti-PD-L1 antibody or antigen-binding fragment thereof that is sufficient for one treatment cycle, and each treatment cycle is 21 days (ie, 3 weeks).

In some embodiments, in the pharmaceutical combination, the mass ratio of the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof is (0.01-30):1, (0.01- 20):1, (0.1-2.5):1, (0.5-1.5):1 or (1-1.25):1; wherein, anti-TIM-3 antibody or antigen-binding fragment thereof and anti-PD-L1 antibody or antigen thereof The combined fragments can be packaged separately or together. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are packaged separately, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof can be performed in single or multiple portions For packaging, anti-PD-L1 antibodies or antigen-binding fragments thereof can be packaged in single or multiple portions. In some embodiments, the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof, are packaged separately, wherein the anti-TIM-3 antibody, or antigen-binding fragment thereof, can be presented in a single portion or in multiple equal portions. For packaging, the anti-PD-L1 antibody or antigen-binding fragment thereof can Packed in single or multiple portions. in some In embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are packaged separately, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof can be provided in a single portion or in multiple aliquots ( For example, 2 equal parts, 3 equal parts, 4 equal parts, 5 equal parts, 6 equal parts, 7 equal parts, 8 equal parts or more) for packaging, the anti-PD-L1 antibody or its antigen-binding fragment can be packaged in a single Packaging in parts or multiple equal parts (such as 2 equal parts, 3 equal parts, 12 equal parts or other equal parts). In some embodiments, an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-L1 antibody, or antigen-binding fragment thereof, are packaged together.

In some embodiments, the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is or an antigen-binding fragment thereof, a pharmaceutical composition prepared as a single or multiple dose suitable for administration to a patient of 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, containing The pharmaceutical composition of the anti-PD-L1 antibody or antigen-binding fragment thereof is prepared to be suitable for administering to a patient 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof Single or multiple doses of fragments. In some embodiments, the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is or an antigen-binding fragment thereof, a pharmaceutical composition prepared suitable for administration to a patient of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about A single dose or multiple doses of an anti-TIM-3 antibody or antigen-binding fragment thereof, containing 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or a range formed by any of the above values, containing anti-PD- Pharmaceutical compositions of L1 antibodies or antigen-binding fragments thereof are prepared suitable for administration to a patient of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg , about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg, about 2300mg, or about 2400mg, or the range formed by any of the above values. Single or multiple doses of PD-L1 antibodies or antigen-binding fragments thereof. In some embodiments, the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is or an antigen-binding fragment thereof, a pharmaceutical composition prepared as a single or multiple dose suitable for administering to a patient about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, containing an anti-PD-L1 antibody or an antigen-binding fragment thereof The pharmaceutical composition is formulated to be suitable for administration to a patient in a single or multiple dose of about 1200 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof.

In another aspect, the present disclosure also provides the use of a pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating tumors. The present disclosure also provides the use of a pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof to treat tumors. The present disclosure also provides methods of treating tumors in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination comprising an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-L1 antibody, or antigen-binding fragment thereof.

In another aspect, the present disclosure provides a kit for treating tumors, the kit comprising a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a medicament containing an anti-PD-L1 antibody or an antigen-binding fragment thereof. compositions, and instructions for using a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof in combination with a pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof to treat tumors.

In another aspect, the present disclosure provides a kit for treating tumors, the kit comprising a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof, and using Description of the pharmaceutical composition for treating tumors.

In another aspect, the present disclosure also provides a pharmaceutical package for treating tumors, which contains individually packaged pharmaceutical compositions in independent containers, wherein one container includes an anti-TIM-3 antibody or an antigen thereof. a pharmaceutical composition that binds the fragment, and includes in a second container a pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof.

In another aspect, the present disclosure also provides a pharmaceutical package for treating tumors, which contains individually packaged pharmaceutical compositions in independent containers, wherein the container includes an anti-TIM-3 antibody or an antigen-binding agent thereof. fragments and pharmaceutical compositions of anti-PD-L1 antibodies or antigen-binding fragments thereof.

In some specific embodiments, in the kit or pharmaceutical package, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is an injectable solution. In some specific embodiments, pharmaceutical compositions containing anti-TIM-3 antibodies or antigen-binding fragments thereof are lyophilized formulations.

In some specific embodiments, in the kit or pharmaceutical package, the pharmaceutical composition containing the anti-PD-L1 antibody or its antigen-binding fragment is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is an injection. In some specific embodiments, the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is a lyophilized preparation.

In some specific embodiments, in the kit or pharmaceutical package, the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-L1 antibody or antigen-binding fragment thereof is an injection. In some specific embodiments, the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-L1 antibody or antigen-binding fragment thereof is a lyophilized preparation.

In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is lung cancer. In some embodiments, the lung cancer includes non-small cell lung cancer or small cell lung cancer. In some embodiments, the non-small cell lung cancer is squamous cell non-small cell lung cancer (also known as squamous cell carcinoma, squamous cell carcinoma, squamous non-small cell lung cancer, or squamous cell carcinoma). In some embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is an adenocarcinoma (also known as lung adenocarcinoma). In some embodiments, the non-small cell lung cancer is large cell carcinoma (also known as lung large cell carcinoma). In some embodiments, the small cell lung cancer is extensive stage small cell lung cancer. In some embodiments, the small cell lung cancer is limited stage small cell lung cancer.

Drug Combination Dosing/Treatment Regimen

In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof can be administered simultaneously, sequentially, and/or alternately. In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered sequentially. In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition, which can be simultaneously, sequentially and/or or alternate administration. In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition and administered sequentially. In some embodiments, in the above uses or methods of treatment, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered first, and then the anti-TIM-3 antibody or antigen-binding fragment thereof is administered. In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition, and the anti-PD-L1 antibody or antigen-binding fragment thereof is first administered. A pharmaceutical composition containing an L1 antibody or an antigen-binding fragment thereof, and then administering a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof. In some embodiments, in the method or use, the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof, are formulated in a single formulation and administered simultaneously.

In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered in the same or different dosage regimens respectively. In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered in different dosage regimens respectively. In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered in the same dosage regimen respectively.

In some embodiments, in the above uses or methods of treatment, the anti-TIM-3 antibody or antigen-binding fragment thereof is every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) Administer once. In a specific embodiment, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks. In a specific embodiment, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 4 weeks. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg each time. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg each time , about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or a dosage within the range formed by any of the above values. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of about 1200 mg or about 1500 mg per administration. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks at 100-1800 mg, 600-1800 mg, 600- A dose of 1500 mg, or 1200-1500 mg of anti-TIM-3 antibody or antigen-binding fragment thereof is administered. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, at about 1200 mg or about 1500 mg of anti-TIM-3 antibody each time or antigen-binding fragments thereof. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of about 1200 mg or about 1500 mg of the anti-TIM-3 antibody or antigen-binding fragment thereof.

In some embodiments, in the above uses or methods of treatment, the anti-PD-L1 antibody or antigen-binding fragment thereof is every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) Administer once. In a specific embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every 3 weeks. In a specific embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every 4 weeks. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at 100-2400 mg, 600-1800 mg, 1000- Doses of 1500 mg, 1000-1200 mg, or 1200-1500 mg are administered. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg each time , about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg, about 2300mg, or about 2400mg, or any of the above values range of doses administered. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of about 1200 mg per administration. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks at 100-2400 mg, 600-1800 mg, 1000- A dose of 1500 mg, 1000-1200 mg, or 1200-1500 mg of anti-PD-L1 antibody or antigen-binding fragment thereof is administered. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, at about 1200 mg of the anti-PD-L1 antibody or antigen thereof. Dosage administration of combined fragments. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every 3 weeks at a dose of about 1200 mg of anti-PD-L1 antibody or antigen-binding fragment thereof.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof have the same or different treatment cycles, respectively. In some specific embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof have the same treatment cycle, such as every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks is a treatment cycle. In some specific embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof have the same treatment cycle, for example, every 3 weeks is a treatment cycle.

In some embodiments, in the above use or treatment method, every 3 weeks is a treatment cycle, and the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered in each treatment cycle. In some embodiments, in the above use or treatment method, every 3 weeks is a treatment cycle, and the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered once in each treatment cycle. . In some embodiments, in the above use or treatment method, every 3 weeks is a treatment cycle, and the anti-TIM-3 antibody or antigen-binding fragment thereof is administered on the 1st day of each treatment cycle, and the anti-TIM-3 antibody or antigen-binding fragment thereof is administered on the 1st day of each treatment cycle. Administer anti-PD-L1 antibodies or antigen-binding fragments thereof. In some embodiments, in the above use or treatment method, every 3 weeks is a treatment cycle, and the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once on the 1st day of each treatment cycle, and once on the 1st day of each treatment cycle. Anti-PD-L1 antibodies or antigen-binding fragments thereof were administered once a day.

In some specific embodiments, in the above uses or treatment methods, every 3 weeks is a treatment cycle, and 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of anti-TIM-3 is administered in each treatment cycle. Antibody or antigen-binding fragment thereof, 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg of anti-PD-L1 antibody or antigen-binding fragment thereof is administered in each treatment cycle. In some specific embodiments, in the above uses or treatment methods, every 3 weeks is a treatment cycle, and about 1200 mg or about 1500 mg of anti-TIM-3 antibody or antigen-binding fragment thereof is administered in each treatment cycle, and in each treatment cycle Approximately 1200 mg of anti-PD-L1 antibody or antigen-binding fragment thereof is administered per cycle. In some specific embodiments, in the above uses or treatment methods, every 3 weeks is a treatment cycle, and about 1200 mg or about 1500 mg of anti-TIM-3 antibody or antigen-binding fragment thereof is administered on the first day of each treatment cycle, Approximately 1200 mg of anti-PD-L1 antibody or antigen-binding fragment thereof is administered on Day 1 of each treatment cycle.

In some embodiments, in each treatment cycle, (0.01-30):1, (0.01-20):1, (0.1-2.5):1, (0.5-1.5):1, or (1-1.25 ): a mass ratio of anti-TIM-3 antibody or antigen-binding fragment thereof and anti-PD-L1 antibody or antigen-binding fragment thereof of 1, administering anti-TIM-3 antibody or antigen-binding fragment thereof and anti-PD-L1 antibody to the subject or antigen-binding fragments thereof. In some embodiments, the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof, are administered in multiple doses or in a single dose. In some embodiments, the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof, are each administered in multiple doses.

In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof can be selected from 0.01 to 50 mg/kg, 0.1 to 40 mg/kg, 0.1 to 35 mg/kg, 0.1 to 30 mg/kg kg, 0.1 to 25mg/kg, 0.1 to 20mg/kg, 0.1 to 15mg/kg, 0.1 to 10mg/kg, 1 to 40mg/kg, 1 to 35mg/kg, 1 to 30mg/kg, 1 to 25mg/kg, 1 to 20mg/kg, 1 to 15mg/kg, 1 to 10mg/kg, 1 to 3mg/kg, 3 to 40mg/kg, 3 to 35mg/kg, 3 to 30mg/kg, 3 to 25mg/kg, 3 to administered to the subject at a dose of 20 mg/kg, 3 to 15 mg/kg, 3 to 10 mg/kg, 10 to 40 mg/kg, 10 to 30 mg/kg, 10 to 25 mg/kg, or 20 to 25 mg/kg; or 1 -2400mg, 20-1800mg, 100-1800mg, 300-1800mg, 600-1600mg, 700-1600mg, 800-1600mg, 900-1600mg, 1000-1600mg, 1100-1600mg, 1200-1600mg, 1300-1600mg, 14 00-1600mg , 1500-1600mg, 600-1500mg, 800-1500mg, 1000-1500mg, 1200-1500mg, 600-1200mg, 800-1200mg, 800mg, 900mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1 600mg, A uniform dose of 1700 mg, or 1800 mg was administered to the subjects.

In some embodiments, in the above uses or treatment methods, the anti-PD-L1 antibody or antigen-binding fragment thereof can be selected from 0.01 to 50 mg/kg, 0.1 to 40 mg/kg, 0.1 to 35 mg/kg, 0.1 to 30 mg/kg kg, 0.1 to 25mg/kg, 0.1 to 20mg/kg, 0.1 to 15mg/kg, 0.1 to 10mg/kg, 1 to 40mg/kg, 1 to 35mg/kg, 1 to 30mg/kg, 1 to 25mg/kg, 1 to 20mg/kg, 1 to 15mg/kg, 1 to 10mg/kg, 1 to 3mg/kg, 3 to 40mg/kg, 3 to 35mg/kg, 3 to 30mg/kg, 3 to 25mg/kg, 3 to administered to the subject at a dose of 20 mg/kg, 3 to 15 mg/kg, 3 to 10 mg/kg, 10 to 40 mg/kg, 10 to 30 mg/kg, 10 to 25 mg/kg, or 20 to 25 mg/kg; or 1 -2400mg, 20-1800mg, 100-1800mg, 300-1800mg, 600-1600mg, 700-1600mg, 800-1600mg, 900-1600mg, 1000-1600mg, 1100-1600mg, 1200-1600mg, 1300-1600mg, 14 00-1600mg , 1500-1600mg, 600-1500mg, 800-1500mg, 1000-1500mg, 1200-1500mg, 600-1200mg, 800-1200mg, 800mg, 900mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1 600mg, 1700mg, or A uniform dose of 1800 mg was administered to the subjects.

In some embodiments, in the above uses or treatment methods, the dosing regimen (e.g., dosing cycle, dosing dose) of the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof and dose adjustments) may be adjusted based on disease severity, disease response, any treatment-related toxicities, and the patient's age and health status. For example, a treatment cycle of anti-TIM-3 antibody or antigen-binding fragment thereof and/or anti-PD-L1 antibody or antigen-binding fragment thereof can be adjusted to 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks. , 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks or 15 weeks.

Anti-TIM-3 antibody or antigen-binding fragment thereof

The anti-TIM-3 antibody or antigen-binding fragment thereof described in the present disclosure includes: heavy chain CDR1 (HCDR1) of the amino acid sequence shown in SEQ ID NO:1, HCDR2 of the amino acid sequence shown in SEQ ID NO:2, SEQ ID NO: HCDR3 with the amino acid sequence shown in SEQ ID NO: 4, LCDR2 with the amino acid sequence shown in SEQ ID NO: 5, and LCDR3 with the amino acid sequence shown in SEQ ID NO: 6. The CDR sequences of anti-TIM-3 antibodies or antigen-binding fragments thereof are shown in Table 1.

Table 1. CDR sequences of anti-TIM-3 antibodies or antigen-binding fragments thereof

It will be understood by those skilled in the art that, unless otherwise specified, the terms "CDR" and "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass those defined by any known scheme. complementarity determining region. Although Table 1 has shown CDR sequences (wherein the CDR regions shown in SEQ ID NO: 1-6 are defined by the AbM numbering system), however, when it comes to defining antibodies with specific CDR sequences defined by certain divisions of this disclosure, The scope of the antibody also includes antibodies defined by CDR sequences converted into any other numbering system definition (such as one or a combination of one or more definitions such as Kabat, Chothia, IMGT or Contact, which are well known in the art). For example, anti-TIM-3 antibodies or antigen-binding fragments thereof comprising the following amino acid sequences are also encompassed within the scope of the anti-TIM-3 antibodies or antigen-binding fragments thereof of the present disclosure: HCDR1 of the amino acid sequence shown in SEQ ID NO: 1, HCDR2 with the amino acid sequence shown in SEQ ID NO:2, HCDR3 with the amino acid sequence shown in ARRYYGYDAMDY (SEQ ID NO:31), LCDR1 with the amino acid sequence shown in SEQ ID NO:4, LCDR2 with the amino acid sequence shown in SEQ ID NO:5 , and LCDR3 of the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO:7 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the heavy chain The variable region, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% of the amino acid sequence shown in SEQ ID NO:8 %, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the light chain variable region. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO:7, and a light chain variable region of the amino acid sequence set forth in SEQ ID NO:8 district. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-TIM-3 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 7, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO. NO:8 shown.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof may further comprise an immunoglobulin constant region, or a fragment, analog, variant or derivative of the constant region. In some embodiments, the heavy chain constant region is derived from a human immunoglobulin heavy chain, such as IgG1, IgG2, IgG3 and IgG4, or a heavy chain of another class of immunoglobulin, preferably an IgG4 heavy chain. In some embodiments, the light chain constant region is from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any modification described herein, such as insertion, deletion, substitution, or chemical modification of amino acids. In some embodiments, the constant region contains mutations that alter effector function. In some embodiments, any amino acid residue of the constant region may be substituted with an amino acid residue of any allotype.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO:9 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the heavy chain , and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% with the amino acid sequence shown in SEQ ID NO:10 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the light chain. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence set forth in SEQ ID NO:9, and a light chain of the amino acid sequence set forth in SEQ ID NO:10. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-TIM-3 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO:9, and the amino acid sequence of the light chain is set forth in SEQ ID NO:10.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure is mAb 50B5 or antigen-binding fragment thereof described in patent application documents with publication number WO2020041520 or CN112566936, or a chimeric antibody of mAb 50B5 or its antigen-binding fragment. Antigen-binding fragments, or humanized antibodies of mAb 50B5 or antigen-binding fragments thereof.

In other embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure is mAb 15B4 or antigen-binding fragment thereof described in patent application documents with publication number WO2020041520 or CN112566936, or a chimeric antibody of mAb 15B4 or An antigen-binding fragment thereof, or a humanized antibody of mAb 15B4, or an antigen-binding fragment thereof.

In other embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure is selected from Sabatolimab, Cobolimab, Surzebiclimab, Roche's RG-7769, Hengrui Medicine's SHR-1702, Agenus' INCAGN-2390, WuXi BC-3402 from Biology, LBL-003 from Verizhibo, LNL-005 from Jianxin Biotech, or BMS-986258 from BMS.

Anti-PD-L1 antibody or antigen-binding fragment thereof

The anti-PD-L1 antibody or antigen-binding fragment thereof described in the present disclosure includes: heavy chain CDR1 (HCDR1) of the amino acid sequence shown in SEQ ID NO: 11 or SEQ ID NO: 21, SEQ ID NO: 12 or SEQ ID NO: HCDR2 with the amino acid sequence shown in SEQ ID NO:13 or HCDR3 with the amino acid sequence shown in SEQ ID NO:23, light chain CDR1 (LCDR1) with the amino acid sequence shown in SEQ ID NO:14 or SEQ ID NO:24, SEQ LCDR2 with the amino acid sequence shown in ID NO:15 or SEQ ID NO:25, and LCDR3 with the amino acid sequence shown in SEQ ID NO:16 or SEQ ID NO:26.

In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: the amino acid sequence shown in SEQ ID NO: 11 HCDR1, HCDR2 with the amino acid sequence shown in SEQ ID NO: 12, HCDR3 with the amino acid sequence shown in SEQ ID NO: 13, LCDR1 with the amino acid sequence shown in SEQ ID NO: 14, LCDR2 with the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 with the amino acid sequence shown in SEQ ID NO:16; or HCDR1 with the amino acid sequence shown in SEQ ID NO:21, HCDR2 with the amino acid sequence shown in SEQ ID NO:22, HCDR3 with the amino acid sequence shown in SEQ ID NO:23, LCDR1 with the amino acid sequence shown in SEQ ID NO:24, LCDR2 with the amino acid sequence shown in SEQ ID NO:25, and LCDR3 with the amino acid sequence shown in SEQ ID NO:26. The CDR sequences of anti-PD-L1 antibodies or antigen-binding fragments thereof are provided in Table 2 below.

Table 2. CDR sequences of anti-PD-L1 antibodies or antigen-binding fragments thereof

It will be understood by those skilled in the art that, unless otherwise specified, the term "CDR" or "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass definitions defined by any one of the known schemes complementarity determining region. Although the CDR regions have been shown in Table 2, when it comes to defining an antibody with specific CDR sequences, the scope of the antibody encompasses any numbering system definition (such as AbM, Kabat, Chothia, IMGT or Contact, etc., which are well known in the art). Antibodies defined by CDR sequences that bind one or more of the definitions).

In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, or 83% identical to the amino acid sequence set forth in SEQ ID NO: 17 or SEQ ID NO: 27 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100 % identity of the heavy chain variable region, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86% with the amino acid sequence shown in SEQ ID NO: 18 or SEQ ID NO: 28 Light chain variable of %, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity district. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises the heavy chain variable region of the amino acid sequence set forth in SEQ ID NO: 17 or SEQ ID NO: 27, and SEQ ID NO: 18 or SEQ The light chain variable region of the amino acid sequence shown in ID NO:28. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO: 17 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the heavy chain The variable region, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% of the amino acid sequence shown in SEQ ID NO:18 %, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the light chain variable region. In other embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO:27. %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity chain variable region, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, A light chain variable region that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO: 17, and a light chain variable region of the amino acid sequence set forth in SEQ ID NO: 18 district. In other embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO: 27, and a light chain variable region of the amino acid sequence set forth in SEQ ID NO: 28. Change area. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-PD-L1 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 17, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO. :18. In other specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-PD-L1 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 27, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO. Shown in NO:28.

In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof may further comprise a constant region of an immunoglobulin, or a fragment, analog, variant or derivative of the constant region. In some embodiments, the heavy chain constant region is from a human immunoglobulin heavy chain, such as IgG1, IgG2, IgG3 and IgG4 or a heavy chain of another class of immunoglobulin, preferably an IgG1 heavy chain. In some embodiments, the light chain constant region is from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any modification described herein, such as insertion, deletion, substitution, or chemical modification of amino acids. In some embodiments, the constant region contains mutations that alter effector function. In some embodiments, any amino acid residue of the constant region may be substituted with an amino acid residue of any allotype, preferably with an amino acid residue of G1m(3) and/or nG1m(1).

In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, or 83% identical to the amino acid sequence set forth in SEQ ID NO: 19 or SEQ ID NO: 29 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100 % identity of the heavy chain, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% with the amino acid sequence shown in SEQ ID NO:20 or SEQ ID NO:30 %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the light chain. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence set forth in SEQ ID NO: 19 or SEQ ID NO: 29, and SEQ ID NO: 20 or SEQ ID NO: 30 The light chain of the amino acid sequence shown. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO: 19 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the heavy chain , and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% with the amino acid sequence shown in SEQ ID NO:20 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the light chain. In other embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO:29. %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity chain, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, A light chain that is 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence set forth in SEQ ID NO: 19, and a light chain of the amino acid sequence set forth in SEQ ID NO: 20. In other embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence set forth in SEQ ID NO:29, and a light chain of the amino acid sequence set forth in SEQ ID NO:30. In some specific embodiments, the heavy chain amino acid sequence of the anti-PD-L1 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 19, and the light chain amino acid sequence is set forth in SEQ ID NO: 20. In other specific embodiments, the heavy chain amino acid sequence of the anti-PD-L1 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO:29, and the light chain amino acid sequence is set forth in SEQ ID NO:30.

The anti-PD-L1 antibodies or antigen fragments thereof of the present disclosure include, but are not limited to, 13C5, 5G11, ch13C5-hlgG1, ch13C5-hlgG4, ch5G11-hlgG1, ch5G11-hlgG4, and hu13C5 described in the patent application documents with publication number WO2016022630 or CN107001463. - hIgG1, hu13C5-hlgG4, hu5G11-hlgG1 or hu5G11-hlgG4 monoclonal antibodies or antigen-binding fragments thereof.

Pharmaceutical compositions containing antibodies or antigen-binding fragments thereof

In some embodiments, an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-L1 antibody, or antigen-binding fragment thereof, are formulated for parenteral administration. In some specific embodiments, the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof, are formulated for administration by intravenous, intramuscular, subcutaneous, or other parenteral routes, For example, for injection or infusion. In some specific embodiments, for intravenous, intramuscular or subcutaneous administration. In some specific embodiments, for intravenous injection or infusion.

Anti-TIM-3 antibodies or antigen-binding fragments thereof and anti-PD-L1 antibodies or antigen-binding fragments thereof can be formulated into suitable dosage forms, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules) , enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (i.e. preparations suitable for injection, such as intramuscular, intravenous, intraperitoneal, subcutaneous), granules, emulsions, suspensions, solutions, Dispersions and dosage forms for sustained-release preparations for oral or parenteral administration. In some specific embodiments, anti-TIM-3 antibodies or antigen-binding fragments thereof and anti-PD-L1 antibodies or antigen-binding fragments thereof can be formulated as injections. In some specific embodiments, anti-TIM-3 antibodies or antigen-binding fragments thereof and anti-PD-L1 antibodies or antigen-binding fragments thereof can be formulated into preparations suitable for intravenous injection (eg, injection solutions or lyophilized preparations).

In some embodiments, the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof, are formulated in a single formulation. In some embodiments, anti-TIM-3 antibodies or antigen-binding fragments thereof, anti-PD-L1 antibodies or antigen-binding fragments thereof are formulated with one or more pharmaceutically acceptable excipients to form a suitable medicament combination.

In some embodiments, the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof, are formulated separately (i.e., each is in the form of a pharmaceutical composition). In some embodiments, an anti-TIM-3 antibody, or antigen-binding fragment thereof, is formulated with one or more pharmaceutically acceptable excipients to form a suitable pharmaceutical composition. In some embodiments, an anti-PD-L1 antibody or antigen-binding fragment thereof is formulated with one or more pharmaceutically acceptable excipients to form a suitable pharmaceutical composition.

In some embodiments, the unit dosage of the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, 240-600 mg or other amounts. Anti-TIM-3 antibody or antigen-binding fragment thereof, for example, about 60 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320 mg, about 360 mg, about 400 mg, about 420 mg, about 440 mg , about 480mg, about 520mg, about 540mg, about 560mg, about 600mg, about 640mg, about 660mg, about 680mg, about 720mg, about 760mg, about 780mg, about 800mg, about 840mg, about 880mg, about 900mg, about 920mg, about 960mg, about 1000mg, about 1020mg, about 1040mg, about 1080mg, about 1120mg, about 1140mg, about 1160mg, about 1200mg, about 1240mg, about 1260mg, about 1280mg, about 1320mg, about 1360mg, about 1380mg, about 1400mg, about 1440mg, An anti-TIM-3 antibody of about 1480 mg, about 1500 mg, about 1520 mg, about 1560 mg, about 1600 mg, about 1620 mg, about 1640 mg, about 1680 mg, about 1720 mg, about 1740 mg, about 1760 mg, or about 1800 mg, or a range formed by any of the above values or antigen-binding fragments thereof. In some embodiments, the unit dose of the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is about 240 mg or about 600 mg of the anti-TIM-3 antibody or antigen-binding fragment thereof.

In some embodiments, the unit dose of the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is 10-1800 mg, 100-1500 mg, 100-1200 mg, 600-1200 mg, 100-600 mg or other amounts of anti-PD-L1 antibody or antigen-binding fragment thereof, such as about 10 mg, about 40 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160mg, about 180mg, about 200mg, about 220mg, about 240mg, about 260mg, about 280mg, about 300mg, about 320mg, about 340mg, about 360mg, about 380mg, about 400mg, about 420mg, about 440mg, about 460mg, about 480mg, About 500mg, about 520mg, about 540mg, about 560mg, about 580mg, about 600mg, about 620mg, about 640mg, about 660mg, about 680mg, about 700mg, about 720mg, about 740mg, about 760mg, about 780mg, about 800mg, about 820mg , about 840mg, about 860mg, about 880mg, about 900mg, about 920mg, about 940mg, about 960mg, about 980mg, about 1000mg, about 1020mg, about 1040mg, about 1060mg, about 1080mg, about 1100mg, about 1120mg, about 1140mg, about 1160 mg, about 1180 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, or an anti-PD-L1 antibody or an antigen-binding fragment thereof within the range formed by any of the above values. In some embodiments, the unit dose of the pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof is about 100 mg or about 600 mg of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

As used herein, "excipient" is used to describe any ingredient other than a compound of the present disclosure. The choice of excipient will depend largely on factors such as the particular mode of administration, the excipient's effect on solubility and stability, and the nature of the dosage form. As used herein, "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Some examples of pharmaceutically acceptable excipients are water, saline, dextrose, glycerol, ethanol, etc., and combinations thereof. In many cases, pharmaceutically acceptable excipients include isotonic agents. Other examples of pharmaceutically acceptable excipients are wetting agents or minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives or buffers, which increase the storage life or effectiveness of the antibody.

In a specific embodiment, the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof is an aqueous injection. In a specific embodiment, the pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof is an aqueous injection. The aqueous injection includes, but is not limited to, aqueous preparations that have not been lyophilized or aqueous preparations reconstituted with lyophilized powder.

In other embodiments, the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is a lyophilized preparation. In other embodiments, the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is a lyophilized preparation. The freeze-dried preparation refers to a preparation prepared from an aqueous solution undergoing a freeze-drying process, in which the substance is first frozen, and then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (secondary drying). process) until the amount of solvent is such that it no longer supports biological activity or chemical reaction. Lyophilized formulations of the present disclosure may also be dried by other methods known in the art, such as spray drying and bubble drying.

In some embodiments, the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof in the pharmaceutical composition containing anti-PD-L1 antibody or antigen-binding fragment thereof is 1-200 mg/mL, 2-150 mg/mL, 4.5 -100mg/mL, 5-80mg/mL, 10-60mg/mL, 10-50mg/mL, or 10-30mg/mL. In some specific embodiments, the concentration of the anti-PD-L1 antibody or antigen-binding fragment thereof is about 4.8 mg/mL, about 5 mg/mL, about 10 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL. mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 80 mg/mL, about 100 mg/mL, or about 120 mg/mL. In some embodiments, the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof is about 4.8 mg/mL. In some embodiments, the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof is about 10 mg/mL. In some embodiments, the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof is about 30 mg/mL. In some embodiments, the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof is about 60 mg/mL.

In some embodiments, the pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof includes: a mass volume concentration of about 1-150 mg/mL anti-PD-L1 antibody or an antigen-binding fragment thereof, and a buffer of 3-50 mM solution, 2-150mg/mL isotonicity regulator/stabilizer and 0.01-0.8mg/mL surfactant, and the pH is about 4.5-6.8.

In a specific embodiment, the pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof includes: (a) an anti-PD-L1 antibody with a mass volume concentration of about 10 mg/mL or about 30 mg/mL, ( b) sucrose at a mass volume concentration of approximately 80 mg/mL, (c) polysorbate 80 at a mass volume concentration of approximately 0.2 mg/mL, (d) histidine at a molar concentration of approximately 10 mM, (e) optionally hydrochloric acid In an appropriate amount, adjust the pH value of the composition to about 5.5.

Mode of administration

The following content does not limit the administration mode of the pharmaceutical combination of the present disclosure.

The components of the pharmaceutical combinations of the present disclosure may be administered individually, or part or all thereof, together, by any suitable route, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). ) application. In some embodiments, the components of the pharmaceutical combinations of the present disclosure may be administered individually, or part or all thereof may be administered together orally or by injection, such as intravenously or subcutaneously. injection.

The components in the pharmaceutical combination of the present disclosure may be formulated independently, or part or all thereof, together into suitable dosage forms, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal, subcutaneous), granules, emulsions, suspensions, solutions, dispersions and preparations for oral or parenteral use Sustained-release formulations for oral administration. In some embodiments, each component of the pharmaceutical combination of the present disclosure may be administered independently, or some or all of them may be co-formulated into an injection.

The components in the pharmaceutical combination of the present disclosure may each independently, or some or all of them may jointly contain pharmaceutically acceptable excipients.

Pharmaceutical combinations of the present disclosure may also include additional therapeutic agents. In one embodiment, the additional therapeutic agent may be a tumor therapeutic agent known in the art.

tumor

In certain aspects, a tumor of the present disclosure is a malignant tumor (i.e., a cancer); by malignant tumor is any malignant and/or invasive growth caused by abnormal cell growth. In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is a refractory, unresectable, recurrent, advanced and/or metastatic solid tumor. In some embodiments, the tumor is an advanced solid tumor.

In some embodiments, the solid tumor is lung cancer. In some embodiments, the lung cancer is refractory, unresectable, recurrent, advanced, and/or metastatic lung cancer.

In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

In some embodiments, the non-small cell lung cancer is squamous cell non-small cell lung cancer (also known as squamous cell carcinoma, squamous cell carcinoma, squamous non-small cell lung cancer, or squamous cell carcinoma). In some embodiments, the non-small cell lung cancer is non-small cell lung cancer whose histology is predominantly squamous cell carcinoma. In some embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is an adenocarcinoma (also known as lung adenocarcinoma). In some embodiments, the non-small cell lung cancer is large cell carcinoma (also known as lung large cell carcinoma). In some embodiments, the non-small cell lung cancer is adenosquamous carcinoma.

In some embodiments, the small cell lung cancer is limited stage small cell lung cancer or extensive stage small cell lung cancer.

In some embodiments, the lung cancer is locally advanced or advanced non-small cell lung cancer. In some embodiments, the lung cancer is recurrent and/or metastatic non-small cell lung cancer. In some embodiments, the lung cancer is advanced, recurrent and/or metastatic non-small cell lung cancer. In some embodiments, the lung cancer is locally advanced, recurrent, and/or metastatic non-small cell lung cancer. In some embodiments, the lung cancer is stage IIIB, stage IIIC or stage IV non-small cell lung cancer.

In some embodiments, the lung cancer is advanced, recurrent and/or metastatic squamous non-small cell lung cancer or non-squamous non-small cell lung cancer (eg, lung adenocarcinoma). In some embodiments, the lung cancer is locally advanced, recurrent and/or metastatic squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer (eg, lung adenocarcinoma). In some embodiments, the lung cancer is stage IIIB, stage IIIC or stage IV squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer (eg, lung adenocarcinoma).

In some embodiments, the lung cancer is locally advanced or advanced small cell lung cancer. In some embodiments, the lung cancer is recurrent and/or metastatic small cell lung cancer. In some embodiments, the lung cancer is advanced, recurrent, and/or metastatic small cell lung cancer. In some embodiments, the lung cancer is locally advanced, recurrent, and/or metastatic small cell lung cancer. In some embodiments, the lung cancer is recurrent and/or metastatic extensive-stage small cell lung cancer. In some embodiments, the lung cancer is recurrent extensive-stage small cell lung cancer.

In some embodiments, the lung cancer is free of driver gene mutations, including but not limited to: EGFR, ALK, ROS1, BRAF, NTRK, MET, and/or KRAS. In some embodiments, the lung cancer is free of EGFR mutations. In some embodiments, the lung cancer does not contain ALK fusion. In some embodiments, the lung cancer is free of ROS1 mutations.

In some embodiments, the non-small cell lung cancer is free of driver gene mutations, including but not limited to: EGFR, ALK, ROS1, BRAF, NTRK, MET, and/or KRAS. In some embodiments, the non-small cell lung cancer is free of EGFR mutations. In some embodiments, the non-small cell lung cancer is free of ALK fusion. In some embodiments, the non-small cell lung cancer is free of ROS1 mutations. In some embodiments, the squamous non-small cell lung cancer or non-squamous non-small cell lung cancer is free of EGFR mutations. In some embodiments, the squamous non-small cell lung cancer or non-squamous non-small cell lung cancer does not have an ALK fusion. In some embodiments, the squamous non-small cell lung cancer or non-squamous non-small cell lung cancer is free of ROS1 mutations.

In some embodiments, the subject with lung cancer has not previously been treated for lung cancer (eg, lacks effective treatment options).

In some embodiments, the subject with lung cancer has not previously received systemic therapy to treat lung cancer.

In some embodiments, the subject with lung cancer has not previously received surgery, radiation therapy, induction chemotherapy, concurrent chemoradiotherapy, adjuvant chemotherapy, and/or immunotherapy to treat lung cancer. In some embodiments, the subject with lung cancer is not suitable for surgical treatment and is not suitable for curative concurrent chemoradiotherapy.

In some embodiments, the subject with lung cancer has previously been treated for lung cancer with one or more different anti-tumor treatments (eg, treatment failed or was not suitable).

In some embodiments, the subject with lung cancer has previously been treated for lung cancer with one or more of surgery, radiation therapy, chemotherapy, and immunotherapy (eg, treatment failed or was not suitable). In some embodiments, the subject with lung cancer has previously been treated for lung cancer with one or more of induction chemotherapy, concurrent chemoradiotherapy, adjuvant chemotherapy, and/or immunotherapy (eg, treatment failure or incompatibility).

In some embodiments, the subject with lung cancer has previously received neoadjuvant or adjuvant therapy (eg, chemotherapy or radiation therapy) to treat lung cancer (eg, treatment failed or was not suitable). In some embodiments, the subject with lung cancer has already had lung cancer treated with chemotherapy (eg, treatment failed or was not suitable). In some embodiments, the subject with lung cancer has already had lung cancer treated with concurrent chemoradiotherapy (eg, treatment failed or was not suitable).

In some embodiments, the subject with lung cancer has not previously received systemic chemotherapy, but has received surgery, radiation therapy, induction chemotherapy, concurrent chemoradiotherapy, and/or adjuvant chemotherapy to treat lung cancer. In some specific embodiments, the subject of lung cancer obtains complete remission or partial remission and then develops disease progression again after undergoing surgical treatment, radiotherapy, induction chemotherapy, concurrent chemoradiotherapy, and/or adjuvant chemotherapy. In some embodiments, the subject with lung cancer has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemoradiotherapy, and/or adjuvant chemotherapy to treat lung cancer, and after stopping treatment for 6 months (e.g., 6, 7, 8, 9, or 10 months) disease progression occurs.

In some embodiments, the subject with non-small cell lung cancer has not previously received systemic chemotherapy, but has received surgery, radiation therapy, induction chemotherapy, concurrent chemoradiotherapy, and/or adjuvant chemotherapy to treat non-small cell lung cancer. In some embodiments, the subject of non-small cell lung cancer obtains complete remission or partial remission and then develops disease progression again after undergoing surgical treatment, radiotherapy, induction chemotherapy, concurrent chemoradiotherapy and/or adjuvant chemotherapy. In some embodiments, the subject with non-small cell lung cancer has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemoradiotherapy, and/or adjuvant chemotherapy to treat non-small cell lung cancer, and 6 months after discontinuing treatment (e.g., 6, 7, 8, 9, or 10 months).

In some embodiments, the subject with lung cancer has already had lung cancer treated with at least one first-line systemic chemotherapy regimen (eg, treatment failed or was not suitable). In some embodiments, the subject with lung cancer has already been treated for lung cancer with a first-line systemic chemotherapy regimen (eg, treatment failed or was not suitable). In some embodiments, the subject with lung cancer has been treated for lung cancer with first or second line treatment regimens (eg, treatment failed or was not suitable).

In some embodiments, the subject with lung cancer has previously received an immune checkpoint (e.g., PD-1, PD-L1, CTLA-4, or PD-L2) inhibitor alone or in combination with platinum-based chemotherapy. (e.g., treatment fails or is not suitable). In some embodiments, the immune checkpoint (e.g., PD-1, PD-L1, CTLA-4, or PD-L2) inhibitor is an antibody directed against an immune checkpoint or an antigen-binding fragment thereof (e.g., targeting PD -1, PD-L1, CTLA-4 or PD-L2 antibodies or antigen-binding fragments thereof).

In some embodiments, the subject with lung cancer has previously received platinum-based chemotherapy (eg, treatment failed or was not suitable).

In some embodiments, the subject of the lung cancer is PD-L1 expression-positive lung cancer. In some embodiments, the subject of the lung cancer is non-small cell lung cancer with positive PD-L1 expression.

In some embodiments, the subject of lung cancer is a non-small cell lung cancer patient without EGFR mutations, ALK fusions, and/or ROS1 mutations. In some embodiments, the subject of lung cancer is a patient with advanced, metastatic or recurrent non-small cell lung cancer in the absence of driver gene mutations (including EGFR mutations, ALK fusions and/or ROS1 mutations). In some embodiments, the subject of the lung cancer is locally advanced (stage IIIB/IIIC), metastatic or recurrent (stage IV) non-cancerous disease without driver gene mutations (including EGFR mutations, ALK fusions and/or ROS1 mutations). Patients with small cell lung cancer. In some embodiments, the subject of the lung cancer is a locally advanced (stage IIIB/IIIC), metastatic or metastatic disease that is positive for PD-L1 expression and does not have driver gene mutations (including EGFR mutations, ALK fusions and/or ROS1 mutations). Patients with recurrent (stage IV) non-small cell lung cancer.

In some embodiments, the subject with lung cancer is a patient with extensive-stage small cell lung cancer who has previously received platinum-based chemotherapy (eg, failed or was ineligible for treatment). In some embodiments, the subject of the lung cancer is a patient with extensive-stage small cell lung cancer who has failed first-line chemotherapy based on platinum-based drugs or is not suitable for first-line chemotherapy based on platinum-based drugs. In some embodiments, the subject of the lung cancer is a patient with recurrent extensive-stage small cell lung cancer who has failed first-line chemotherapy based on platinum-based drugs or is not suitable for first-line chemotherapy based on platinum-based drugs.

The present disclosure also provides the following specific embodiments, but the protection scope of the present disclosure is not limited thereto:

Embodiment 1. A pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody or an antigen-binding fragment thereof comprises: SEQ HCDR1 with the amino acid sequence shown in ID NO:1, HCDR2 with the amino acid sequence shown in SEQ ID NO:2, HCDR3 with the amino acid sequence shown in SEQ ID NO:3, LCDR1 with the amino acid sequence shown in SEQ ID NO:4, SEQ ID NO LCDR2 with the amino acid sequence shown in SEQ ID NO: 5, and LCDR3 with the amino acid sequence shown in SEQ ID NO: 6.

Embodiment 2. The pharmaceutical combination according to Embodiment 1, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO:7. chain variable region, and a light chain variable region whose amino acid sequence is at least 95% identical to the amino acid sequence shown in SEQ ID NO:8.

Embodiment 3. The pharmaceutical combination according to embodiment 1 or 2, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 9 The heavy chain, and the light chain whose amino acid sequence has at least 95% identity with the amino acid sequence shown in SEQ ID NO:10.

Embodiment 4. The pharmaceutical combination according to any one of embodiments 1-3, wherein the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200mg, or 240-600mg.

Embodiment 5. The pharmaceutical combination according to any one of embodiments 1-4, wherein the unit dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is 10-1800 mg, 100-1500 mg, 100-1200 mg, 600-1200mg, or 100-600mg.

Embodiment 6. The pharmaceutical combination according to any one of embodiments 1-5, wherein the mass ratio of the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof is ( 0.01-30):1, (0.01-20):1, (0.1-2.5):1, (0.5-1.5):1 or (1-1.25):1.

Embodiment 7. The pharmaceutical combination according to any one of embodiments 1-6, wherein the pharmaceutical combination is suitable for administration in a single treatment cycle, which includes 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of anti-TIM-3 antibody or antigen-binding fragment thereof.

Embodiment 8. The pharmaceutical combination according to Embodiment 7, wherein the pharmaceutical combination includes 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg of anti-PD-L1 antibody or antigen thereof Combine fragments.

Embodiment 9. The pharmaceutical combination according to any one of embodiments 1-8, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises:

(a) HCDR1 with the amino acid sequence shown in SEQ ID NO:11, HCDR2 with the amino acid sequence shown in SEQ ID NO:12, HCDR3 with the amino acid sequence shown in SEQ ID NO:13, LCDR1 with the amino acid sequence shown in SEQ ID NO:14 , LCDR2 of the amino acid sequence shown in SEQ ID NO:15, and LCDR3 of the amino acid sequence shown in SEQ ID NO:16; or

(b) HCDR1 with the amino acid sequence shown in SEQ ID NO:21, HCDR2 with the amino acid sequence shown in SEQ ID NO:22, HCDR3 with the amino acid sequence shown in SEQ ID NO:23, LCDR1 with the amino acid sequence shown in SEQ ID NO:24 , LCDR2 with the amino acid sequence shown in SEQ ID NO:25, and LCDR3 with the amino acid sequence shown in SEQ ID NO:26.

Embodiment 10. The pharmaceutical combination according to any one of embodiments 1-9, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises:

(a) A heavy chain variable region whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 17, and a light chain whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 18 variable region; or

(b) A heavy chain variable region whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 27, and a light chain whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 28 Variable area.

Embodiment 11. The pharmaceutical combination according to any one of embodiments 1-10, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises:

(a) A heavy chain whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 19, and a light chain whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 20; or

(b) A heavy chain whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 29, and a light chain whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 30.

Embodiment 12. The pharmaceutical combination according to any one of embodiments 1-11, wherein the pharmaceutical combination is used to treat tumors.

Embodiment 13. The pharmaceutical combination of embodiment 12, wherein the tumor is a solid tumor.

Embodiment 14. The pharmaceutical combination according to embodiment 13, wherein the solid tumor is lung cancer.

Embodiment 15. The pharmaceutical combination according to embodiment 14, wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

Embodiment 16. Use of the pharmaceutical combination according to any one of embodiments 1-11 in the preparation of a medicament for treating tumors.

Embodiment 17. The use of embodiment 16, wherein the tumor is a solid tumor.

Embodiment 18. The use of embodiment 17, wherein the solid tumor is lung cancer.

Embodiment 19. The use of embodiment 18, wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

Embodiment 20. The use according to any one of embodiments 16-19, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof can be used simultaneously, sequentially and /or alternate administration.

Embodiment 21. The use according to embodiment 20, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered sequentially.

Embodiment 22. The use of any one of embodiments 16-21, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks The anti-TIM-3 antibody or antigen-binding fragment thereof is administered once, optionally, at a dose of 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg each time.

Embodiment 23. The use of any one of embodiments 16-22, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks The anti-PD-L1 antibody or antigen-binding fragment thereof is administered once, optionally, at a dose of 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg each time.

Embodiment 24. A kit for treating tumors, comprising the pharmaceutical combination according to any one of embodiments 1-15.

Technical effect

In general, using the pharmaceutical combinations of the present disclosure described above will help:

(1) Produce better efficacy in reducing tumor growth or even eliminating tumors than either drug in the combination given alone;

(2) Provide for administration of smaller amounts than either drug in the combination administered alone;

(3) Provide a treatment that is well tolerated in patients and has fewer adverse effects and/or complications than either drug administered alone;

(4) Provide better disease control rates among treated patients;

(5) Provide longer survival (such as median survival, progression-free survival or overall survival) for the patients being treated;

(6) Provide the treated patients with longer survival (such as median survival, progression-free survival or overall survival) compared with standard chemotherapy;

(7) Provide longer duration of disease response (DOR); and/or

(8) Compared with any drug in the combination administered alone, it has good anti-tumor activity and shows a better anti-tumor synergistic effect.

The disclosed drug combination and treatment plan have good curative effects in the treatment of lung cancer (including non-small cell lung cancer and small cell lung cancer). It has a beneficial effect in at least one of ORR, DCR, DOR, PFS, OS, tolerability and side effects.

Definition and Description

Unless otherwise stated, the following terms used in this disclosure have the following meanings. A particular term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in accordance with its ordinary meaning in the art. Where a trade name appears in this disclosure, it is intended to refer to its corresponding trade name or its active ingredient.

As used herein, the term "pharmaceutical combination" refers to the simultaneous or sequential administration of two or more active ingredients (including administration as the respective active ingredients themselves, or as their respective pharmaceutically acceptable salts or esters). such as derivatives, prodrugs or compositions). The active ingredients may each be administered to the subject simultaneously as a single formulation, or each as a single formulation sequentially in any order. Alternatively, all of the active ingredients are formulated in a single formulation and administered to the subject simultaneously.

The term "fixed combination" refers to the active components (e.g., anti-TIM-3 antibody or antigen-binding fragment thereof and anti-PD-L1 antibody or antigen-binding fragment thereof) in a fixed total dose or dose ratio, or as a single entity, drug combination The drug or preparation is administered to the subject at the same time.

The term "non-fixed combination" refers to two or more active components administered to a subject simultaneously, concurrently or sequentially as independent entities (e.g. pharmaceutical compositions, preparations), wherein the active components administered to the subject achieve therapeutic effectiveness. quantity level. Examples of non-fixed combinations include cocktail therapy, for example, administration of three or more active ingredients. In non-fixed combinations, the individual active ingredients may be packaged, sold or administered as entirely separate pharmaceutical compositions. The "non-fixed combination" also includes the combined use of "fixed combinations" between "fixed combinations" or "fixed combinations" with any one or more independent entities of the active ingredients.

As used herein, the term "antibody" refers to an antigen-binding protein having at least one antigen-binding domain. Antibodies and fragments thereof of the present disclosure A segment may be an entire antibody or any fragment thereof. Thus, the antibodies and fragments thereof of the present disclosure include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof. Examples of antibodies and antigen-binding fragments thereof include monospecific antibodies, bispecific antibodies, multispecific antibodies, Fab fragments, Fab' fragments, F(ab)' ₂ fragments, Fv fragments, isolated CDR regions, single-chain Fv molecules (scFv) and other antibody fragments known in the art. The anti-TIM-3 antibodies and anti-PD-L1 antibodies and antigen-binding fragments thereof disclosed herein can be of the IgGl, IgG2, IgG3 or IgG4 isotype. The term "isotype" refers to the class of antibody encoded by the heavy chain constant region genes. The anti-TIM-3 antibodies and antigen-binding fragments thereof and the anti-PD-L1 antibodies and antigen-binding fragments thereof of the present disclosure can be derived from any species, including but not limited to mouse, rat, rabbit, primate, llama, and people. The anti-TIM-3 antibodies and antigen-binding fragments thereof and the anti-PD-L1 antibodies and antigen-binding fragments thereof of the present disclosure may be murine antibodies, chimeric antibodies, humanized antibodies, or fully human antibodies. Unless otherwise stated, "antibodies" in this disclosure include entire antibodies and any antigen-binding fragments (or "antigen-binding portions") or single chains thereof. A conventional "whole antibody" is a glycoprotein containing two heavy (H) chains and two light (L) chains linked by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region consists of three domains, namely CH1, CH2 and CH3. Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region consists of one domain, CL. The VH and VL regions can also be divided into hypervariable regions, namely complementarity determining regions (CDR), and framework regions (FR) with relatively conserved sequences. Each VH and VL are composed of three CDRs and four FRs respectively, from the amino end to the carboxyl end: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant region of an antibody can mediate binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system. Meanwhile, as is understood by those skilled in the art, special "whole antibodies", such as Nanobodies, have only heavy (H) chains and no light (L) chains.

An "antigen-binding fragment" or "antibody-binding portion" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding an antigen (eg, TIM-3 or PD-L1). It has been demonstrated that the antigen-binding function of an antibody can be performed by fragments of the entire antibody. Examples encompassed by the term "antigen-binding portion/fragment" of an antibody include: (i) Fab fragments: monovalent fragments consisting of VL, _VH , CL and CH1 domains; ₍ ii) F(ab')2 fragments , a bivalent fragment containing two Fab fragments connected by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of an antibody single arm ; (v) a dAb fragment consisting of a VH domain (see Ward et al., Nature. 341:544-546 (1989)); (vi) an isolated complementarity determining region (CDR); and (vii) a Nanobody, A heavy chain variable region containing a single variable domain and two constant domains. In addition, although the two domains VL and VH of the Fv fragment are encoded by different genes, recombinant methods can be used to connect VH and VL into a single protein chain through synthetic linkers, in which VL and VH pair to form a monovalent molecule (called a single-chain Fv (scFv); see, for example, Bird et al., Science. 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85:5879-5883 (1988)). These single chain antibodies are also encompassed by the term antigen-binding portion/fragment. Furthermore, recombinant polypeptides, fusion proteins and immunoconjugates comprising such antigen-binding portions/fragments are also encompassed by the term antigen-binding portions/fragments.

A "chimeric antibody" is an antibody that has at least a portion of a heavy chain variable region derived from one species and at least a portion of a light chain variable region; and at least a portion of a constant region derived from another species. . For example, in one embodiment, a chimeric antibody may comprise a murine variable region and a human constant region.

A "humanized antibody" is an antibody that contains complementarity determining regions (CDRs) derived from a non-human antibody; and framework and constant regions derived from a human antibody. For example, anti-TIM-3 antibodies and anti-PD-L1 antibodies can comprise CDRs derived from one or more murine antibodies and human framework and constant regions. Provided herein are exemplary humanized antibodies. Additional anti-TIM-3 antibodies or variants thereof comprising the HCDR and LCDR provided herein can be generated using any human framework sequences and are also included in the present disclosure. Additional anti-PD-L1 antibodies or variants thereof comprising the HCDR and LCDR provided herein can be generated using any human framework sequences and are also included in the present disclosure. In one embodiment, framework sequences suitable for use in the present disclosure include those that are structurally similar to the framework sequences provided herein. Additional modifications can be made in the framework regions to improve the properties of the antibodies provided herein. Such additional framework modifications may include chemical modifications; point mutations to reduce immunogenicity or remove T cell epitopes; or mutations back to residues in the original germline sequence. In some embodiments, such modifications include those corresponding to mutations exemplified herein, including back mutations to germline sequences. For example, in one embodiment, one or more amino acids in the human framework regions of the VH and/or VL of the humanized antibodies provided herein are backmutated to the corresponding amino acids in the parent murine antibody.

The term "identity" is also called consistency. "Percent (%) identity" of an amino acid sequence refers to the sequence to be compared after aligning it with the specific amino acid sequence shown herein and introducing gaps if necessary to achieve the maximum percent sequence identity, and without regard to When any conservative substitution is included as part of sequence identity, the percentage of amino acid residues in the aligned sequence that are identical to the amino acid residues of the specific amino acid sequence shown herein. Alignment of amino acid sequences for identity can be performed using various methods within the scope of the art, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. One skilled in the art can determine appropriate parameters for aligning sequences, including Any algorithm required to obtain maximal alignment over the full length of the compared sequences.

The term "treatment" refers to an attempt to alter the natural course of a disease in a treated individual, and may be a clinical intervention performed for prevention or during the course of clinical pathology. The desired effects of treatment include but are not limited to preventing the occurrence or recurrence of the disease, alleviating the symptoms of the disease, reducing any direct or indirect pathological consequences of the disease, preventing the metastasis of the disease, slowing down the progression rate of the disease, improving or alleviating the state of the disease, and prolonging the disease. Frequency and duration of asymptomatic periods, and prognosis for resolution or improvement of disease.

The term "therapeutically effective amount" means (i) treating a specified disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying as used herein An amount of a compound of the present disclosure that is associated with the onset of one or more symptoms of a particular disease, condition or disorder. The amount of active material (e.g., an antibody or antigen-binding fragment thereof of the present disclosure) that constitutes a "therapeutically effective amount" may vary depending on factors such as the disease state, age, sex, and weight of the individual, as well as the therapeutic agent or combination of therapeutic agents. The ability in an individual to elicit a desired response. Therapeutically effective amounts may also be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

The term "administering" or "administering" means the physical introduction to a subject of a pharmaceutical composition containing a therapeutic agent using any of a variety of methods and delivery systems known to those skilled in the art.

Routes of administration of the antibody or antigen-binding fragment thereof (e.g., anti-TIM-3 antibody or antigen-binding fragment thereof or anti-PD-L1 antibody or antigen-binding fragment thereof) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other gastric Parenteral route of administration, such as by injection or infusion. The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic , intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion , and in vivo electroporation. Administration may also be performed, eg, once, multiple times, and/or over one or more extended time periods.

The term "flat dose" is used to mean the dose administered to a patient without regard to the patient's weight or body surface area (BSA). A unified dose is therefore stated as an absolute amount of agent (eg, anti-TIM-3 antibody or antigen-binding fragment thereof or anti-PD-L1 antibody or antigen-binding fragment thereof) rather than as a mg/kg dose. For example, a 60 kg person and a 100 kg person will receive the same dose of antibody (eg, 1200 mg or 1500 mg of anti-TIM-3 antibody or antigen-binding fragment thereof, 1200 mg of anti-PD-L1 antibody or antigen-binding fragment thereof).

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

As used herein, the terms "subject," "patient," or "subject" are used interchangeably. "Subject," "patient," or "subject" includes any human or non-human animal. The term "non-human animals" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the term "subject," "patient," or "subject" is a mammal. In some embodiments, the subject, patient or subject is a mouse. In some embodiments, the subject, patient or subject is human.

As used herein, "about" means within the range of error that one of ordinary skill in the art would determine is acceptable for a particular value, which depends in part on how the value is measured or determined, ie, the limitations of the measurement system. For example, "about" may mean within 1 or more than 1 standard deviation in accordance with practice in the art. Alternatively, "about" may mean up to ±5%, such as ±2%, ±1%, or ±0.5% of a given numerical range. When a specific value is given in the disclosure or claims, unless otherwise stated, the meaning of "about" shall be considered to be within an acceptable error range for that specific value. In this article, unless otherwise stated, the values of step parameters or conditions are modified by "about" by default.

As used herein, "combination" or "used in combination" means that two or more active substances may be administered to a subject simultaneously, each as a single formulation, or each as a single formulation, sequentially in any order. Alternatively, all of the active ingredients are formulated in a single formulation and administered to the subject simultaneously.

The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven tablets, one tablet is a single dose; or a bottle of injection is a single dose. The term "multiple doses" consists of a plurality of single doses. “Unit dose” refers to the dose of active ingredient contained in the smallest packaging unit containing a certain amount of medicine. For example, the dose of antibody contained in a bottle of antibody injection is a unit dose.

The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present disclosure or a pharmaceutical combination thereof and a pharmaceutically acceptable excipient. The purpose of pharmaceutical compositions is to facilitate administration to a subject of a compound of the present disclosure or a pharmaceutical combination thereof. Herein, the terms "pharmaceutical composition" and "preparation" have the same meaning and are used interchangeably.

The term "recurrent" cancer is a cancer that reappears at the original site or at a distant site after responding to initial treatment, such as surgery. A "locally recurrent" cancer is a cancer that appears after treatment in the same location as a previously treated cancer.

The term "metastatic" cancer refers to cancer that has spread from one part of the body, such as the lungs, to another part of the body.

The term "refractory" refers to a situation in which a subject or mammal has residual cancer cells in its body even after intensive treatment.

The term "first-line treatment" refers to the first or standard choice of drug treatment based on the patient's condition.

The term "treatment failure" is defined as disease progression or recurrence during or after the last treatment.

The term "PD-L1 positive" or "PD-L1 expression positive" referring to cell surface PD-L1 expression refers to the proportion of cells in a test tissue sample containing tumor cells and tumor-infiltrating immune cells above which the Samples were assessed as expressing cell surface PD-L1. For cell surface expression as determined by immunohistochemistry (IHC) (e.g., with mAb 28-8), PD-L1 positive tumors or tumors positive for PD-L1 expression means at least about 0.01%, at least about 0.5%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, or at least about 30% of the total cells express PD-L1. PD-L1 positive tumors or PD-L1 expression positive tumors may also be described herein as PD-L1 expressing tumors. In other embodiments, PD-L1 positive tumors or PD-L1 expression positive tumors mean, at least about 0.1%-20%, at least about 0.1%-10%, at least about 1%, at least about 5%, at least about 1% % or a range of 1%-5% of the total cells express PD-L1 on the cell surface. In one embodiment, PD-L1 positive tumor or PD-L1 expression positive tumor means that at least about 1% of the total cells express PD-L1 on the cell surface. In one embodiment, PD-L1 positive tumor or PD-L1 expression positive tumor means that at least about 1% of the total number of tumor cells or tumor-infiltrating immune cells express PD-L1 on the cell surface.

In this document, unless the context clearly dictates otherwise, singular terms encompass plural referents and vice versa.

All patents, patent applications, and other identified publications are expressly incorporated by reference herein for purposes of description and disclosure. These publications are provided solely because their disclosures preceded the filing date of this disclosure. All statements as to the date of these documents or representations of the contents of these documents are based on information available to the applicant and do not constitute any admission as to the correctness of the date of these documents or the contents of these documents. Furthermore, any reference herein to these publications does not constitute an admission that the publications form part of the common general knowledge in the art in any country.

Description of the drawings

Figure 1 shows the tumor volume (mm ³ ) of mice in each group on D11. P values are compared by Mann-Whitney test. * indicates P<0.05, and P<0.05 is defined as a statistically significant difference;

Figure 2 shows the tumor weight (g) of mice in each group on D11. P values are compared by Mann-Whitney test. * indicates P<0.05, and P<0.05 is defined as a statistically significant difference.

Example

For the sake of clarity, examples are further used to illustrate the disclosure, but the examples do not limit the scope of the disclosure.

The entire contents of WO2020041520 or CN112566936 patent application documents are incorporated into this disclosure. The heavy chain amino acid sequence of the anti-TIM-3 antibody in the following examples is as shown in SEQ ID NO: 9 of the present disclosure, and the light chain amino acid sequence is as shown in SEQ ID NO: 10 of the present disclosure.

The preparation and purification methods of the anti-PD-L1 antibodies in the present disclosure have been recorded in the patent application documents with publication numbers WO2016022630 or CN107001463, and the entire contents of the WO2016022630 or CN107001463 patent application documents are incorporated into the present disclosure. The hu5G11-hlgG1 in the following examples is the hu5G11-hlgG1 in WO2016022630 or CN107001463. The heavy chain amino acid sequence of hu5G11-hlgG1 is as shown in SEQ ID NO:19 of the present disclosure, and the light chain amino acid sequence is as shown in SEQ ID of the present disclosure. NO:20 shown.

Example 1: The efficacy of anti-TIM-3 antibodies and anti-PD-L1 antibodies on lung cancer HCC827 subcutaneous transplanted tumors

HCC827 cells were purchased from the Cell Bank of the Chinese Academy of Sciences. The cells were cultured in RPMI-1640 medium containing 10% fetal calf serum to the exponential growth phase. The cells were collected for later use. Human peripheral blood mononuclear cells (HuPBMC) were purchased from Shanghai Rubai Biotechnology Co., Ltd. The cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, and then the cells were collected for use. NCG mice (NOD/ShiLtJ Gpt-Prkdc em26Cd52Il2rgem26Cd22/Gpt Gpt) aged 6-7 weeks were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. and were raised in an SPF-level barrier environment. After the NCG mice adapted to the environment, each NCG mouse was subcutaneously inoculated with 8 × 10 ⁶ HCC827 cells. After the tumors grew to 100-200 mm ³ , they were divided into 5 groups according to the tumor volume, with 8 mice in each group. Each mouse was injected intravenously (IV) with 5 × 10 ⁶ HuPBMC, and the next day each mouse was intraperitoneally injected with hIgG4 (purchased from Sino Biological), anti-TIM-3 antibody, hu5G11-hlgG1, or anti-TIM-3 antibody. +hu5G11-hIgG1, administered once each on D0, D3, D7, and D10 for a total of 4 times. The administration volume is 10 mg/kg body weight. D0 indicates the time of the first administration. The dosage is as shown in Table 3. Show.

Use a vernier caliper to measure the tumor diameter twice every week, calculate T/C (%) or tumor inhibition rate TGI (%) through the following formula, and examine the effect of the drug on the tumor. effects on tumor growth. At the end of the experiment, when the end point of the experiment was reached, or when the tumor volume reached 1500 mm ³ , the animals were anesthetized with CO ₂ and sacrificed, and then the tumors were dissected and removed. The calculation formula of tumor volume (V) is: V=1/2×a×b ² , where a and b represent the tumor length and width respectively; T/C (%)=(TT ₀ )/(CC ₀ )×100, Among them, T and C are the tumor volumes of the treatment group and hIgG4 group at the end of the experiment; T ₀ and C ₀ are the tumor volumes of the treatment group and hIgG4 group at the beginning of the experiment; tumor inhibition rate (TGI) (%) = 100-T/C (%).

During the experiment, the tumor-bearing mice in each group tolerated the drugs well, and no symptoms such as obvious weight loss occurred. The results are shown in Table 3 and Figure 1-2. On D11, the average tumor volumes of mice in groups 2 and 3 were 589.7±59.6mm ³ and 703.4±58.9mm ³ respectively, and the tumor inhibition rates were 35% and 35%, respectively. 19%; the average tumor volume of mice in group 4 was 546.4±58.2mm ³ and the tumor inhibition rate was 42%; the average tumor volume of mice in group 5 was 488.7±70.7mm ³ and the tumor inhibition rate was 51% (P <0.05, compared with group 1); in addition, the tumor weight of mice in group 5 was not only significantly lower than that of mice in group 1, but also significantly lower than that of mice in groups 2, 3 and 4. The tumor weight of mice (see Figure 2); indicates that the combination of anti-TIM-3 antibody and hu5G11-hlgG1 has a synergistic anti-tumor effect.

Table 3. The efficacy of anti-TIM-3 antibodies and anti-PD-L1 antibodies on lung cancer HCC827 subcutaneous transplanted tumors

Note: P value is compared with group 1 through two-tailed Student's t test, and P<0.05 is defined as a statistically significant difference.

Example 2: Clinical trial of non-small cell lung cancer

1. Selection criteria:

Only those who meet all the following inclusion criteria can be enrolled in this trial:

(1) The subjects voluntarily joined this study and signed the informed consent form.

(2) Age: 18-75 years old (when signing the informed consent form).

(3)ECOG PS score: 0-1 points.

(4) The expected survival period is more than 3 months.

(5) Enrolled patients meet the following criteria:

Cohort 1: patients with advanced first-line NSCLC with positive PD-L1 expression,

Cohort 2: patients with advanced immunorefractory NSCLC with positive PD-L1 expression,

1) Patients with locally advanced (stage IIIB/IIIC), recurrent or metastatic (stage IV) NSCLC who are not suitable for surgical treatment and are not suitable for radical concurrent chemoradiation and chemotherapy confirmed by histology or cytology;

2) For non-squamous non-small cell lung cancer, testing proves that there is no EGFR mutation, ALK fusion, or ROS1 mutation (for squamous non-small cell lung cancer, patients with known gene mutations are excluded, and testing is not mandatory for those with unknown status);

3) PD-L1 expression positive proportion ≥1% [TC (tumor cells) or IC (immune cells) ≥1%];

4) Cohort 1 advanced first-line patients: have not received systemic anti-tumor treatment for advanced disease. Patients are allowed to have received neoadjuvant/adjuvant chemotherapy or radiotherapy or concurrent chemoradiotherapy in the past, but the interval between disease recurrence and completion of the last treatment must be at least 6 months;

5) Patients with advanced immune resistance in Cohort 2: who have failed or are intolerant to at least immune checkpoint (including but not limited to PD-1 or PD-L1) inhibitor treatment (combination or sequential or single drug allowed, sequential Refers to: first receive platinum-containing chemotherapy followed by immune checkpoint inhibitor therapy and maintenance). Number of previous lines of treatment for advanced disease: 1-2. For neoadjuvant/adjuvant chemotherapy or radiotherapy or concurrent chemoradiotherapy, if the disease progresses during treatment or within 6 months after stopping treatment, it should be counted as a first-line treatment option.

(6) Confirmed to have at least one measurable lesion according to RECIST 1.1 standards.

(7) The main organ functions are normal, that is, the following standards are met:

1) Routine blood examination standards (no blood transfusion or correction with hematopoietic stimulating factor drugs within 7 days before the examination):

a. Hemoglobin (HGB) ≥90g/L;

b. Neutrophil absolute value (NEUT) ≥1.5×10 ⁹ /L;

c. Platelet count (PLT) ≥90×10 ⁹ /L;

2) Biochemical examinations must meet the following standards:

a. Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN) (Gilbert syndrome patients: TBIL ≤ 3 × ULN);

b.Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN. Those with primary hepatobiliary tumors or liver metastases: ALT, AST ≤ 5 × ULN;

c. Serum creatinine (CR) ≤ 1.5 × ULN or creatinine clearance rate (CCR) ≥ 60 mL/min;

3) Coagulation function must meet the following standards:

Activated partial thrombin time (APTT), international normalized ratio (INR), prothrombin time (PT) ≤ 1.5 × ULN (no anticoagulant treatment);

4) Thyroid function tests must meet the following standards:

Thyroid-stimulating hormone (TSH) ≤ ULN; if abnormal, the levels of triiodothyronine (T3) and thyroxine (T4) should be examined. If T3 and T4 levels are normal, you can be selected;

5) Cardiac color ultrasound evaluation: left ventricular ejection fraction (LVEF) ≥50%.

(8) Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study period and within 6 months after the end of the study; serum pregnancy / The urine pregnancy test is negative and must be non-lactating subjects; male subjects must agree to use contraceptive measures during the study period and within 6 months after the end of the study period.

2. Experimental drugs and dosing regimen

The hu5G11-hIgG1 injection was infused first, and then the anti-TIM-3 antibody injection was infused.

hu5G11-hIgG1 injection (specification: 600mg/20mL/bottle, and/or 100mg/10mL/bottle): 3 weeks is a treatment cycle, through intravenous infusion, on the first day of each treatment cycle, 1200mg hu5G11-hIgG1 The dose is administered once.

Anti-TIM-3 antibody injection (specification: 240mg/4mL/bottle, and/or 600mg/10mL/bottle): 3 weeks is a treatment cycle, through intravenous infusion, 1200mg, 1500mg on the first day of each treatment cycle or a dose of 1800 mg anti-TIM-3 antibody administered once.

3. Evaluation criteria

The efficacy evaluation standard is based on RECIST 1.1, and the iRECIST standard is used to confirm the efficacy.

4. End point indicators

Objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall survival (OS), etc.;

Pharmacokinetic/pharmacodynamic related indicators: pharmacokinetic (PK) parameters, immunogenicity (ADA) incidence, receptor occupancy (RO), etc.;

Adverse event incidence: the occurrence of all adverse events (AE), serious adverse events (SAE) and treatment-related adverse events (TEAEs), as well as abnormal laboratory test indicators.

5.Results

Preliminary research results show that anti-TIM-3 antibody combined with hu5G11-hIgG1 can safely and effectively treat advanced non-small cell lung cancer (especially advanced non-small cell lung cancer with positive PD-L1 expression). After combined treatment with anti-TIM-3 antibody + hu5G11-hIgG1, the clinical efficacy and survival benefit of the patient can be significantly improved, the patient's condition can be relieved and controlled, the progression of the disease can be slowed down, and the patient's progression-free survival and overall survival can be prolonged. Expect. It shows the advantages of anti-TIM-3 antibody combined with hu5G11-hIgG1 in the treatment of advanced non-small cell lung cancer.

Example 3: Clinical trial of small cell lung cancer

1. Selection criteria:

Only those who meet all the following inclusion criteria can be enrolled in this trial:

(1) The subjects voluntarily joined this study and signed the informed consent form;

(2) Age: 18-75 years old (when signing the informed consent form); ECOG PS score: 0-1 points; expected survival period is more than 3 months;

(3) Patients with pathologically confirmed extensive-stage small cell lung cancer (according to the Veterans Administration Lung Cancer Association Study Group, VALG stage);

(4) Failure or intolerance to at least first-line platinum-containing chemotherapy regimens for extensive-stage small cell lung cancer;

(5) Previous exposure to immune-mediated treatments is allowed, including but not limited to other anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-PD-L2 antibodies, excluding therapeutic anti-cancer vaccines;

(6) Brain metastasis: must be asymptomatic or treated and the disease has been stable for at least 1 month after stopping steroids and anticonvulsants (before treatment in this study). Patients suspected of having brain metastases during the screening period should undergo brain CT/MRI before entering this study;

(7) Confirmed to have at least one measurable lesion according to RECIST 1.1 standards;

(8) The main organ functions are normal, that is, the following standards are met:

1) Routine blood examination standards (no blood transfusion or correction with hematopoietic stimulating factor drugs within 7 days before the examination):

a. Hemoglobin (HGB) ≥90g/L;

b. Neutrophil absolute value (NEUT) ≥1.5×10 ⁹ /L;

c. Platelet count (PLT) ≥100×10 ⁹ /L;

2) Biochemical examinations must meet the following standards:

a. Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN) (Gilbert syndrome patients: TBIL ≤ 3 × ULN);

b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; patients with primary hepatobiliary tumors or tumor liver metastases: ALT, AST ≤ 5 × ULN;

c. Serum creatinine (CR) ≤ 1.5 × ULN or creatinine clearance rate (CCR) ≥ 60 mL/min.

3) Coagulation function must meet the following standards: activated partial thrombin time (APTT), international normalized ratio (INR), prothrombin time (PT) ≤ 1.5 × ULN (not receiving anticoagulant therapy);

4) Thyroid function tests must meet the following standards:

Thyroid stimulating hormone (TSH) ≤ ULN; if abnormal, T3 and T4 levels should be examined. If T3 and T4 levels are normal, you can be selected.

5) Cardiac color ultrasound evaluation: left ventricular ejection fraction (LVEF) ≥50%.

(9) Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study period and within 6 months after the end of the study; serum pregnancy / The urine pregnancy test is negative and must be non-lactating subjects; male subjects must agree to use contraceptive measures during the study period and within 6 months after the end of the study period.

2. Experimental drugs and dosing regimen

The hu5G11-hIgG1 injection was infused first, and then the anti-TIM-3 antibody injection was infused.

hu5G11-hIgG1 injection (specification: 600mg/20mL/bottle, and/or 100mg/10mL/bottle): 3 weeks is a treatment cycle, through intravenous infusion, 1200mg hu5G11-hIgG1 on the first day of each treatment cycle The dose is administered once (dosing time window: ±3 days).

Anti-TIM-3 antibody injection (specification: 240mg/4mL/bottle, and/or 600mg/10mL/bottle): 3 weeks is a treatment cycle, through intravenous infusion, on the first day of each treatment cycle, 1200mg or A dose of 1500 mg of anti-TIM-3 antibody was administered once (dosing time window: ±3 days).

3. Evaluation criteria

The efficacy evaluation standard is based on RECIST 1.1, and the iRECIST standard is used to confirm the efficacy.

4. End point indicators

Objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall survival (OS), etc.;

Pharmacokinetic/pharmacodynamic related indicators: pharmacokinetic (PK) parameters, immunogenicity (ADA) incidence, receptor occupancy (RO), etc.;

Adverse event incidence: the occurrence of all adverse events (AE), serious adverse events (SAE) and treatment-related adverse events (TEAEs), as well as abnormal laboratory test indicators.

5.Results

Preliminary research results show that anti-TIM-3 antibody combined with hu5G11-hIgG1 can safely and effectively treat extensive-stage small cell lung cancer (especially extensive-stage small cell lung cancer that has failed or is intolerant to first-line platinum-containing chemotherapy regimens). After combined treatment with anti-TIM-3 antibody + hu5G11-hIgG1, the clinical efficacy and survival benefit of the patient can be significantly improved, the patient's condition can be relieved and controlled, the progression of the disease can be slowed down, and the patient's progression-free survival and overall survival can be prolonged. At this stage, some patients can achieve partial response PR, and the overall disease control rate is high DCR. The advantages of anti-TIM-3 antibody combined with hu5G11-hIgG1 in the treatment of extensive-stage small cell lung cancer are shown. Specific exemplary results are as follows:

(1)Exemplary results

1) Diagnostic results: The patient was diagnosed with small cell lung cancer in the upper lobe of the right lung, extensive stage.

2) Previous treatment: The patient's disease progressed after 6 cycles of EC (etoposide + carboplatin) regimen.

3) Treatment plan: Every 3 weeks is a treatment cycle. On the first day of each treatment cycle, 1200 mg of hu5G11-hIgG1 injection is first intravenously infused, and then 1200 mg of anti-TIM-3 antibody injection is intravenously infused.

4) Treatment effect and evaluation:

Screening period: target lesion 71 mm;

2 cycles of treatment: target lesion 40mm;

According to the efficacy evaluation standards, so far, the patient’s best treatment effect is PR (partial remission).

Claims (15)

1. A pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody or an antigen-binding fragment thereof comprises: SEQ ID NO: 1 HCDR1 of the amino acid sequence shown in SEQ ID NO:2, HCDR2 of the amino acid sequence shown in SEQ ID NO:3, HCDR3 of the amino acid sequence shown in SEQ ID NO:3, LCDR1 of the amino acid sequence shown in SEQ ID NO:4, SEQ ID NO:5 The amino acid sequence of LCDR2, and the amino acid sequence of LCDR3 shown in SEQ ID NO:6.
2. The pharmaceutical combination according to claim 1, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region whose amino acid sequence has at least 95% identity with the amino acid sequence shown in SEQ ID NO:7 , and a light chain variable region whose amino acid sequence is at least 95% identical to the amino acid sequence shown in SEQ ID NO:8.
3. The pharmaceutical combination according to claim 1 or 2, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: a heavy chain whose amino acid sequence has at least 95% identity with the amino acid sequence shown in SEQ ID NO:9, and a light chain whose amino acid sequence is at least 95% identical to the amino acid sequence shown in SEQ ID NO:10.
4. The pharmaceutical combination according to any one of claims 1-3, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises:

   (a) HCDR1 with the amino acid sequence shown in SEQ ID NO:11, HCDR2 with the amino acid sequence shown in SEQ ID NO:12, HCDR3 with the amino acid sequence shown in SEQ ID NO:13, LCDR1 with the amino acid sequence shown in SEQ ID NO:14 , LCDR2 of the amino acid sequence shown in SEQ ID NO:15, and LCDR3 of the amino acid sequence shown in SEQ ID NO:16; or

   (b) HCDR1 with the amino acid sequence shown in SEQ ID NO:21, HCDR2 with the amino acid sequence shown in SEQ ID NO:22, HCDR3 with the amino acid sequence shown in SEQ ID NO:23, LCDR1 with the amino acid sequence shown in SEQ ID NO:24 , LCDR2 with the amino acid sequence shown in SEQ ID NO:25, and LCDR3 with the amino acid sequence shown in SEQ ID NO:26.
5. The pharmaceutical combination according to any one of claims 1-4, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises:

   (a) A heavy chain variable region whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 17, and a light chain whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 18 variable region; or

   (b) A heavy chain variable region whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 27, and a light chain whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 28 Variable area.
6. The pharmaceutical combination according to any one of claims 1-5, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises:

   (a) A heavy chain whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 19, and a light chain whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 20; or

   (b) A heavy chain whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 29, and a light chain whose amino acid sequence is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 30.
7. The pharmaceutical combination according to any one of claims 1-6, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are formulated for parenteral administration Preferably, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are formulated for intravenous, intramuscular or subcutaneous administration; optionally,

   The anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are formulated in a single preparation, or the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or its Antigen-binding fragments are formulated separately.
8. The pharmaceutical combination according to any one of claims 1-7, wherein the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600mg;

   Optionally, the unit dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is 10-1800 mg, 100-1500 mg, 100-1200 mg, 600-1200 mg, or 100-600 mg.
9. The pharmaceutical combination according to any one of claims 1 to 8, wherein the mass ratio of the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof is (0.01-30) :1, (0.01-20):1, (0.1-2.5):1, (0.5-1.5):1 or (1-1.25):1.
10. The pharmaceutical combination according to any one of claims 1 to 9, wherein the pharmaceutical combination is suitable for administration within a single treatment cycle and includes 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg. anti-TIM-3 antibody or antigen-binding fragment thereof, and 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg of anti-PD-L1 antibody or antigen-binding fragment thereof.
11. Use of the pharmaceutical combination according to any one of claims 1 to 10 in the preparation of medicaments for treating tumors.
12. The use according to claim 11, wherein the tumor is a solid tumor; preferably, the solid tumor is lung cancer; more preferably, the The lung cancer is non-small cell lung cancer or small cell lung cancer.
13. The use according to claim 11 or 12, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof can be administered simultaneously, sequentially and/or alternately.
14. The use according to any one of claims 11-13, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; optional Preferably, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg each time.
15. The use according to any one of claims 11-14, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; optional Preferably, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg each time.